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Mechanism of substrate recognition and release of human SGLT2

Author

Listed:
  • Wenhao Cui

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine)

  • Zejian Sun

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University
    Peking University)

  • Jiaxuan Xu

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine)

  • Xiaoyu Liu

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University)

  • Yunlu Kang

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine)

  • Lei Chen

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University
    Peking University
    Peking University)

Abstract

Glucose is a vital energy source essential for life and human health. Sodium-glucose cotransporter 2 (SGLT2) is a sodium-glucose symporter that utilizes the electrochemical gradient of sodium to reabsorb glucose from kidney filtrate back into circulation. SGLT2 plays a crucial role in maintaining blood glucose homeostasis and is an important drug target for type 2 diabetes. Despite its significance, the mechanisms by which SGLT2 recognizes and releases substrates during its transport cycle remain largely unknown. Here, we present structures of human SGLT2 in complex with a glucose analogue in the occluded conformation at 2.6 Å resolution, revealing a detailed hydrogen bonding network at the substrate binding site that governs substrate recognition. Additionally, structures of SGLT2 in both the substrate-bound inward-facing conformation and the substrate-free inward-facing conformations illustrate the structural changes that occur during substrate release into cytosol. Our structural analysis, combined with mutagenesis results, identifies specific polar interactions that are essential for maintaining the outer and inner gates in their closed conformations.

Suggested Citation

  • Wenhao Cui & Zejian Sun & Jiaxuan Xu & Xiaoyu Liu & Yunlu Kang & Lei Chen, 2025. "Mechanism of substrate recognition and release of human SGLT2," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62421-6
    DOI: 10.1038/s41467-025-62421-6
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    References listed on IDEAS

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    1. Solveig G. Schmidt & Mette Galsgaard Malle & Anne Kathrine Nielsen & Søren S.-R. Bohr & Ciara F. Pugh & Jeppe C. Nielsen & Ida H. Poulsen & Kasper D. Rand & Nikos S. Hatzakis & Claus J. Loland, 2022. "The dopamine transporter antiports potassium to increase the uptake of dopamine," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Yange Niu & Wenhao Cui & Rui Liu & Sanshan Wang & Han Ke & Xiaoguang Lei & Lei Chen, 2022. "Structural mechanism of SGLT1 inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Yunlu Kang & Lei Chen, 2022. "Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Jiaxin Tan & Yuan Xiao & Fang Kong & Xiaochun Zhang & Hanwen Xu & Angqi Zhu & Yiming Liu & Jianlin Lei & Boxue Tian & Yafei Yuan & Chuangye Yan, 2024. "Molecular basis of human noradrenaline transporter reuptake and inhibition," Nature, Nature, vol. 632(8026), pages 921-929, August.
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